Design, Synthesis, Antiviral Evaluation, and Molecular Dynamics Simulation Studies of New Spirocyclic Thiopyrimidinones as Anti HCoV‐229E

Abstract

The current pandemic threat presented by viral pathogens like SARS-CoV-2 (COVID-19) suggests that virus emergence and dissemination are not geographically confined. As a result, the quest for antiviral agents has become critical to control this pandemic. In the current study, we provide a novel family of spirocyclic thiopyrimidinone derivatives whose cytotoxicity and antiviral efficacy were investigated against human coronavirus 229E (HCoV-229E) as a model for the Coronaviridae family. We utilized MTT and cytopathic effect (CPE) inhibitory tests on green monkey kidney (vero-E6) cell lines. The new molecules showed varied degrees of antiviral activity against the vero-E6 cell lines with minimal cytotoxicity. With a high level of a selective index (SI = 14.8), compound 9 showed outstanding inhibitory ability and could effectively suppress the human coronavirus 229E. Molecular dynamics simulation (MD) studies were performed to measure the interaction and stability of the protein-ligand complex in motion. The MD results for the most active compound 9 explored remarkable interactions with the binding pockets of the main protease (Mpro) of SARS-CoV-2 enzyme confirming the results gained from in vitro experiments. ADMET properties were also predicted for all the tested compounds. All these results demonstrated that the novel spirocyclic thiopyrimidinone derivatives would have the potential to be safe, low-cost chemical compounds that might be used as a novel therapeutic option for Coronaviridae viruses like COVID-19.

Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies

“…To compute the antiviral efficiency percentage of any substance, we use the subsequent formula: antiviral efficiency = [(cell controls’ mean optical density minus virus controls)/(the test optical density minus virus controls)] × 100. Based on these data, the 50% CPE inhibitory dose (ID 50 ) was calculated [ 16 , 57 ].…”

Dual action of epigallocatechin-3-gallate in virus-induced cell Injury

“…Based on prior reports [ 41 , 43 ], cells were seeded in a 96-well plate at a density of 2 × 10 5 cells/well and then treated for 72 h at 37 °C in a humidified environment of 5% CO 2 with two-fold concentrations of EGCG (7.5–0.0146 mM). Following the incubation period, the medium was replaced with 100 μl of MTT solution (5 mg/ml) and incubated at 37 °C for 4 h. After 30 min at 37 °C, the MTT solution was changed with 50 μl of acidified isopropanol.…”

Synthesis and Antiproliferative Properties of Some Spirocyclic Pyrimidine Hydrazones

“…In our recent work, we gained promising results dealing with the synthesis of bioactive derivatives based on spirocyclic pyrimidines for their application as antibacterial agents against multi-drug resistant pathogens [36] or as antiviral agents against the human coronavirus 229E. [37] Among these compounds, a series of hydrazone derivatives (4 m-r) was synthesized (Scheme 1) [36] using benzaldehyde and its monosubstituted derivatives (involving 4-Cl, 4-F, 4-Me, 4-OMe, and 4-pyridinecarboxaldehyde). Inspired by these results, we aim, in the current study, to synthesize new derivatives of hydrazones (4 a-l) for the potential to investigate their anticancer properties (Scheme 1).…”